TY - JOUR AB - The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (ErgcEC-Het) and inducible homozygous deficient mice (ErgiEC-KO), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease. AU - Dufton,NP AU - peghaire,CR AU - Osuna-Almagro,L AU - Raimondi,C AU - Kalna,V AU - Chuahan,A AU - Webb,G AU - Yang,Y AU - Birdsey,GM AU - Lalor,P AU - Mason,JC AU - Adams,D AU - Randi,AM DO - 10.1038/s41467-017-01169-0 EP - 14 PY - 2017/// SN - 2041-1723 SP - 1 TI - Dynamic regulation of canonical TGFβ signaling by endothelial transcription factor ERG protects from liver fibrogenesis T2 - Nature Communications UR - http://dx.doi.org/10.1038/s41467-017-01169-0 UR - https://www.nature.com/articles/s41467-017-01169-0 UR - http://hdl.handle.net/10044/1/50493 VL - 8 ER -